Prosthesis of foam polyurethane and collagen and uses thereof

ABSTRACT

An implantable medical prosthesis is provided having a uniform mixture of foam polyurethane and collagen. The prosthesis can be shaped into an elongated hollow body tube useful for implantation in an animal. Alternatively, the prosthesis can be shaped into biocompatible units useful as soft-tissue replacements or as matrices for sustained-release vehicles.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 07/281,364 filed Dec. 8, 1988, now abandoned.

FIELD OF THE INVENTION

The present invention is in the field of medical prostheses. Morespecifically, the present invention is directed to a prosthesis composedof a uniform mixture of collagen and foam polyurethane which is suitablefor use, for example, as a vascular prosthesis or soft tissuereplacement.

BACKGROUND OF THE INVENTION

The use of prostheses for the replacement of blood vessels and otheranatomical ducts is of great interest in medicine and veterinary work.The use of biomaterials in prostheses and biomedical devices is reviewedin Hanker, J. S. et al., Science 242:885-892 (1988), and by Gebelein, C.G., "Prosthetic and Biomedical Devices" in Kirk-Othmer, ConciseEncyclopedia of Chemical Technology, M. Grayson, ed., Wiley & Sons,1985, pp. 965-968, both incorporated herein by reference. To beacceptable in a given application, a prosthesis must exhibit the propermechanical properties and bio-acceptable composition for the givenapplication. For example, vascular prostheses must provide abio-acceptable surface which is conducive to cellular attachment andsustained blood flow, but yet is strong enough not to split or tear.Especially it is critical that the vascular prosthesis not tear alongthe body of the prosthesis or at the site of the sutures.

Collagen has been proposed as a biomaterial which has many propertiesdesirable of a medical prosthesis. Collagen is a family of fibrousproteins that have been classified into a number of structurally andgenetically distinct types (Stryer, L. Biochemistry, 2nd Edition, W. H.Freeman & Co., 1981, pp. 184-199).

Type I collagen is the most prevalent form. Type I collagen is found inskin, tendons, and bones and consists of two subunits of α1(I) collagenand one subunit of a different sequence termed α2. Other types ofcollagen have three identical subunits or chains, each consisting ofabout 1,000 amino acids.

Different tissues express different types of collagen, depending upontheir structural needs. For example, type II collagen is found incartilage, type III collagen is found in blood vessels and thecardiovascular system, and type IV collagen is localized in basementmembranes. Collagen is a unique protein in that it forms insolublefibers that have a high tensile strength.

Tubes made of pure collagen have been proposed for use as vascularprostheses (Noishiki, Y. et al., U.S. Pat. No. 4,690,973; Chu, G. U.S.Pat. No. 4,655,980; and Huc, A. J. Am. Leather Chem. Assoc. 80:195-212(1985)); arterial prostheses (Maurer, P. et al., Eur. Surg. Res.Sep.-Oct., p. 90, (1983)); ureteral replacements, (Tachibana, M. et al.,J. Urology 133:866-869 (1985)); and as a microencapsulation material forthe oral administration or implantation of controlled release substances(Huc, A., et al., U.S. Pat. Nos. 4,711,783 and 4,670,014; Sanders, N.J., Chem. Eng. News, Apr. 1, 1985, p. 30-48).

However, the mechanical properties of prostheses made solely of collagenare not satisfactory for many purposes due to a tendency to tear orsplit. Especially, prostheses made solely of collagen are notsatisfactory for replacement of vessels with a small diameter (Huc, A.,J. Am. Leather Chem. Assoc. 80:195-212 (1985)). Attempts to strengthenthe mechanical characteristics of collagen by fixing or tanning it havenot been successful. Grillo found collagen tubes too weak to allow finesilk suturing without splitting at the sites of the needle puncture(Grillo, H. C. et al., J. Surg. Res II (1): 69-82 (1962)).

To avoid the mechanical deficiencies of collagen tubular prostheses,prostheses composed of other polymers such as Dacron and polyurethanehave been prepared (Robert, A.-M. et al., Pathol. Biol. (Paris)24-Supp.:42-47 (1976); Maupepit, P., EP Patent Application PublicationNo. 058623); as well as combinations of plastics and polyurethane(Hanson, S. R., U.S. Pat. No. 4,687,482; Mano, H. et al.. U.S. Pat. No.Re. 31,618; and Buddecke, E., DE Patent No. 1,494,939). However, theseprostheses lack the biocompatability of collagen, and do not promote therevascularization of the prosthesis in the manner that collagen does(Huc, A., J. Am. Leather Chem. Assoc. 80: 195-212 (1985)). In addition,prostheses made solely from synthetic materials often evoke a foreignbody response, suffer from fatigue or are potentially toxic orcarcinogenic (Grillo, H. C. et al., J. Surg. Res. II (1):69-82 (1982)).

A composition comprising foam polyurethane and collagen has been used asa contraceptive sponge (Vorhaur, B., Biofluid Mechanics, vol. 2, 1980,Plenum, pp. 93-124) and to promote neovascularization (Lamberton, P. etal., ASAIO Abstracts 16:29 (1987)). Lamberton also proposed the use of acollagen impregnated polyurethane sponge to promote neovascularizationin endocrine or hepatic transplantation, soft tissue prosthesis, bonegraft or drug delivery systems (Lamberton, P. et al., ASAIO Abstracts16:29 (1987)).

But there remains a need for a prosthesis which provides thebio-compatibility of collagen with the required pliancy and mechanicalstrength for use in medical applications such as conduits for thereplacement of a missing, diseased or damaged biological vessel andespecially a biological vessel with a small diameter.

SUMMARY OF THE INVENTION

The present invention provides a composition comprising foampolyurethane and collagen which can be shaped into biocompatible unitsfor implantation as prostheses wherein the collagen is an integral partof the matrix which forms the backbone of the prosthetic structure.

The present invention further provides a tubular prosthesis useful forimplantation in an animal comprising an elongated hollow body tube, saidhollow body tube being open at both ends and defining a confined-flowpassageway, wherein said prosthesis comprises a uniform mixture of foampolyurethane and collagen, of one or more layers; the vascularprosthesis so produced has the strength and pliancy consistent withreplacement of the human artery.

The present invention further provides a composition of collagen andfoam polyurethane that can be shaped into biocompatible units, of one ormore layers, for use as soft-tissue replacements or as matrices forsustained-release vehicles. Such biocompatible units may also supplymedicinal substances such as hormones or drugs at a controlled rate tothe host.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph representative of a typical tensile strength responseof a canine carotid artery.

FIG. 2 is a graph representative of results typical of the tensilestrength of a polyurethane/collagen graft (1.0 mg/ml collagen), singlelayer.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a composition comprising a mixture of foampolyurethane and collagen which is capable of being shaped into a widevariety of bio-compatible conduits and especially into a tube, suitablefor implantation as an artificial device, a prosthesis, to replace amissing, diseased or damaged part of the body of a human or otheranimal. Additionally this composition of foam polyurethane and collagenis capable of forming a vascular prosthesis with mechanicalcharacteristics consistent with replacement of the human artery.Additionally, this composition of foam polyurethane and collagen iscapable of forming implantable biocompatible units capable of use assoft-tissue replacements and as sustained-release vehicles.

The prosthesis composition of the present invention derives from theinventors' discovery that foam polyurethane is capable of correcting themechanical deficiencies of collagen prostheses. The prostheses of theinvention, comprising a mixture of foam polyurethane and collagen, forthe first time allow the implantation of a prosthesis with thebio-compatibility advantages of collagen and the mechanical advantagesof polymerized foam polyurethane. The incorporation of collagen duringthe cross-linking reaction makes collagen an integral chemical componentof the structure of the molded polyurethane prosthesis. Surprisingly,unexpected and advantageous mechanical properties are realized whencollagen is incorporated into the polyurethane matrix as the prosthesisis formed. These unexpected and advantageous mechanical propertiesinclude unexpected strength and resistance to tearing at the site of thesutures.

By prosthesis is meant an artificial device designed to replace amissing, diseased or damaged part of the body of an animal.

By a prosthesis containing at least one "layer" of the composition ofthe invention (a uniform mixture of foam polyurethane and collagen) ismeant a prosthesis containing at least one discrete ply or strata of thecomposition of the invention. This layer may be joined, in the finalproduct, to additional layers wherein each layer surrounds the other butwherein each layer, that is each ply or stratum, had originally beenmolded separately or at a separate time, from the other layers. Thelayers containing the composition of the invention may be directlyadjacent to each other or physically separated by a layer(s) of asubstance with a differing composition. A layer or layers of a substancewith a composition different from that of the composition of theinvention may also be used to "coat" the prosthesis on its inner and/orouter surface. For example, the layered prosthesis may be molded so asto contain an outer layer containing polyurethane and silicone.

By animal or host is meant a human or other member of the kingdomAnimelia which is developed enough to have separate organ systems and acirculatory system.

By biocompatible is meant compatible with living tissue; a biocompatiblesubstance does not harm the host nor does it evoke a severe foreign bodyreaction. In a severe foreign body reaction, the function of theprosthesis becomes severely compromised by the host's response to itspresence.

By implant is meant to fix or set securely in a living site, such as intissue or as a replacement for a biological vessel or conduit, aprosthesis which promotes tissue growth, slow release of a medicinalsubstance, or formation of an organic union with the surrounding tissue.

By conduit is meant a channel through which something (as a fluid) flowsor is conveyed.

By tubular is meant the form of a tube; that is, resembling a hollow,sometimes elongated, cylinder. When the prosthesis of the invention isin the shape of a hollow tube, it has an inner and an outer surface; theinner surface being that surrounding the liquid being conveyed throughthe prosthesis.

By uniform mixture is meant a mixture which has the same composition orphysical properties throughout the entire physical structure of themixture.

By sustained-release vehicle is meant a biocompatible vehicle capable ofsupplying a prolonged release of substance such as a drug or hormone,for a relatively long period of time, such as hours, days, months oreven years.

The chemistry of the urethanes is reviewed in Billmeyer, F. W., Textbookof Polymer Science, Wiley & Sons, 1984, incorporated herein byreference. Polyurethanes are polymers containing the group: ##STR1## andare typically formed through the reaction of a diisocyanate and aglycol:

    xOCNRCNO+xHOR'OH→-[OCONHRNHCOOR'-].sub.x.

In the production of polyurethane foams, excess isocyanate groups in thepolymer react with water or carboxylic acids to produce carbon dioxidewhich `blows` the foam at the same time that crosslinking is occurring.This results in a crosslinked product containing bubbles of trappedcarbon dioxide. As discussed in Billmeyer, supra, upon curing, thepolyurethane foam may be either flexible or rigid depending on thenature of the polymer and the type of crosslinking. Because of the rapidcuring of the polyurethane, it is especially compatible with reactioninjection molding (RIM) wherein the polymerization and crosslinking areeffected simultaneously with molding of the material into its finalshape.

Urethane foams are made in several steps. First, there is a basicintermediate which comprises a polyether made of poly(1,4-butyleneglycol), sorbitol polyether, or other polyethers of a molecular weightaround 1,000 daltons. If flexible foams are desired, this intermediateis bifunctional and if rigid foams are desired this intermediate ispolyfunctional.

The basic intermediate reacts with an aromatic diisocyanate, usuallytolylenediisocyanate, to give a prepolymer. Catalysts are then added tothe prepolymer to effect rapid production of foam as described abovewith crosslinking forming through the synthesis of urea bridges.Crosslinking increases the melting point, decreases the solubility andmoisture regain and strengthens the interstrand bonding.

In some cases, a low-boiling inert liquid such as a fluorocarbon hasbeen used to replace the blowing action of carbon dioxide. This resultsin a foam with some altered characteristics, such as a lower thermalconductivity due to the entrapped fluorocarbon gas, when compared to thecarbon dioxide blown foams. Alternatively, a two-step synthesis may beused, wherein the foam is first partly frothed with the inert gas andthen foamed with carbon dioxide.

In the one-step process for the synthesis of flexible foams, thepolyether intermediate tolylenediisocyanate and catalysts are mixed justbefore foaming.

Hypol 2002 (sold by W. R. Grace and Co., Lexington, Mass.) is preferredbecause it is a special medical grade of polyurethane prepolymer which,upon mixing with water and other aqueous solutions, produces ahydrophilic foam having no extractable toluene diamine, toluenedisocyanate or other primary aromatic amines. Foam extracts of thisproduct are inert in the body and are not mutagenic. In addition, thecured product has been shown to be a good biomaterial for supportingcellular growth and, potentially, a good biomaterial to serve as ablood/surface interface. Hypol is described in U.S. Pat. No. 4,127,200,incorporated herein by reference. An elastic biomaterial is necessaryfor the fabrication of implantable medical devices such as vasculargrafts, small diameter vascular grafts, atrial patches, ventricularpatches, prosthetic valve cusps and arterial patches.

Additionally, the foamed polyurethane (polyurethane isocyanate) may bemanufactured such that the end product may be biodegradable, thusallowing the product to be slowly absorbed by the host. The material canbe engineered to any point along a scale of from rapidly biodegradableto biodurable where biodurable is defined as a substance as stable asDacron in the host. Biodegradability, of the final polymer, isdetermined by the inclusion, in the reacting liquid, of chemical species(or groups) that are scissionable (or "digestible") in a livingmammalian system. An example of how to increase the biodegradability ofthe final polymer would be to react the Hypol with lactic acid groupsthat can be broken down in vivo. In that example, the total number ofscissionable lactic acid bonds per unit material would determine thetime course of degradation.

Any non-antigenic, non-specific collagen such as, for example, asynthesized collagen is useful in the invention. When used as a vasculargraft, type III collagen is preferred because it is the type of collagennative to blood vessels. Vascular collagen (type III) can be obtainedcommercially from Sigma Chemical Company, St. Louis, Mo. The collagensolution is dissolved in 0.005M acetic acid solution. The collagen goesinto solution readily, in the cold (4°-6° C.) in 24-48 hours.

The prosthesis described herein has at least three essentialcharacteristics. First, the prosthesis is compatible with animal tissuesand does not provoke a severe foreign body reaction. Second, theprosthesis is strong enough to a) resist tearing at the site of sutureand b) resist splitting due to physiological pressures of a liquid suchas blood being conveyed through it. Third, the prosthesis potentiallypromotes neovascularization of the implant site and may provide asurface conducive to the ingrowth and proliferation of cells fromadjacent areas and the development of new tissue. These threecharacteristics are achieved by including collagen in the reactionmixture at the time of chemical cross-linking of the polyurethane duringformation or molding of the prosthetic structure.

The present invention further provides a tubular prosthesis useful forimplantation in an animal comprising an elongated hollow body tube, saidhollow body tube being open at both ends and defining a confined-flowpassageway.

In a preferred embodiment, the confined-flow passageway of saidprosthesis has an inner diameter of 10 mm or less.

In another preferred embodiment, the confined-flow passageway of saidprosthesis has an inner diameter of 5 mm or less.

Especially, the composition is compatible with grafts of a smalldiameter; that is, with a graft having an inner diameter of 5.0 mm orsmaller. A standard size graft of 6.0 mm or greater such as thosecommonly used in clinical peripheral vascular surgery is also compatiblewith the composition of the invention.

Preferably, the prepolymer is Hypol 2002 and is mixed with a stocksolution of saline or Lactated Ringer's Solution containing 1. 0 mg/mlcollagen, 2 units/ml heparin, and 2 ml of 0.1%/liter of Triton X-100 asa surfactant. The use of 2 ml/liter of 0.1% Triton X-100 as a surfactantensures that the polyurethane has closed-cell foam when activated asdescribed below. Lactated Ringer's solution U.S.P. is composed of 600 mgof sodium chloride; 300 mg of sodium lactate; 30 mg of potassiumchloride; and 20 mg of calcium chloride in a total of 100 ml ofdistilled water.

Preferably, Hypol 2002 is added to the solution of vascular collagen ina 1:1 volumetric ratio such as 1 ml Hypol 2002 per ml of the collagensolution and the reaction between collagen and polyurethane is allowedto proceed, the reaction proceeding in the mold. In a preferredembodiment the solutions of Hypol 2002 and collagen are mixed at 4°-6°C. and the reaction time is complete within two minutes.

The polyurethane is activated as a function of temperature, releasingCO₂. The temperature and hence the rate at which CO₂ is releasedcontrols the number and size of the CO₂ bubbles in the final product,and thus the foaminess, permeability and strength of the prosthesiswall. In a preferred embodiment, the reaction is run at 4°-6° C. andresults in a product in which the bubbles are small and uniformlydistributed throughout the prosthesis.

A bubble is considered to be small if its diameter is less than 0.2 mm,of medium size if its diameter is between 0.2-0.5 mm, and large if itsdiameter is 1 mm or greater. Large bubbles are undesirable and tend tolend to failure of the prosthesis at the site of the large bubble.

The molded prosthesis has a compliance at least as good as a humanartery where compliance is understood by those in the art to be the easewith which a vessel segment can expand to hold a larger volume.Compliance is generally looked upon as an indicator of the overallhealth of a given blood vessel. The foam polyurethane-collagen grafts ofthe invention are considerably more "compliant," that is, "stretchy,"than a natural vessel and have the ability to be elongated to twicetheir original length with not much plastic deformation. Plasticdeformation is that phase where a material is stretched beyond itsability to recoil to normal form or to snap back. It is the part of thedeformation curve just prior to failure or breakage of the material.

Triton X-100 is a nonionic detergent composed of various polyoxyethyleneethers and other surface-active compounds. Triton X-100 is availablecommercially and is produced by Rohm & Haas Co. In this invention,Triton X-100 serves only as a surfactant and does not participate in thereaction between collagen and polyurethane. Therefore, other surfaceactive agents which are non-ionic such as Brij, Tween or silicon oilswould be useful in this capacity. A surface active compound may not benecessary and may be omitted if desired. The decision on whether or notto include a surface active compound will depend upon the performance ofthe collagen-polyurethane solution in forming a suitable prosthesis. Forexample, prostheses made using the synthetic collagen "Vitrogen"(Collagen Corp.), do not require the addition of a surface activecompound in the solution forming the molded prosthesis to yield adesirable product.

Heparin serves as an endothelial cell growth factor and as ananticoagulant and is not a required participant in the reaction betweencollagen and polyurethane. The presence of heparin in the collagensolution at the time of the reaction ensures that the prosthesis will bethoroughly impregnated with the compound. As an endothelial cell growthfactor, heparin serves to encourage the establishment of endothelialcells as a confluent endothelial lining of the prosthesis afterimplantation. When seeded prior to implantation, a lining of endothelialcells reduces the thrombogenicity of a prosthesis (Shindo, S., et al.,J. Vasc. Surg. 6:325-332 (1987)).

In a highly preferred embodiment, the prosthesis of the invention is an"active" prosthesis as opposed to a "pasive" prosthesis. An "activeprosthesis" performs a mechanical function. Examples of mechanicalfunctions include (a) the mechanical function of confined transport of afluid, and especially blood, (b) the mechanical function of fluid flowregulation, for example, opening and/or closing an aperture, such as avalve, and (c) the mechanical function of expansion and/or contractionin harmony with the physiological demands of the supporting environment,for example, the expansion and contraction requirements of an aorticpatch.

The prostheses prepared by the method of the invention can be stored indistilled water with antibiotics, antimycotics and the like to preventcontamination of the graft. Alternatively, the prostheses can be driedand then ethylene oxide sterilized. The prostheses may also besterilized by gamma radiation.

In one embodiment, the wall thicknesses between the natural biologicalvessel and the prosthesis are essentially the same. The wall thicknessof the prosthesis is limited only by that thickness which is required toprovide sufficient mechanical strength so as not to tear, split orproduce undesired fluid or hemodynamic flow problems under physiologicalconditions. It is not necessary to exactly match the thickness of thenatural biological vessel with that of the prosthesis.

In a preferred embodiment, a prosthesis is constructed which containsmore than one layer of the collagen-polyurethane mixture, each layersurrounding the other. In a highly preferred embodiment, a prosthesis ofat least two layers is constructed and the outer layer includes asilicone elastomer in place of the collagen. A prosthesis with twolayers can be constructed, for example, by molding the first prosthesislayer around a mandrel and then molding a second layer around thestructure of the first prosthesis without removing the mandrel. By thismethod the two layers are "joined." In addition, those of ordinary skillin the art will recognize other ways of joining two molded layers of thecomposition of the invention, such as chemically linking two moldedunits. The advantage of a prosthesis comprising layers of thecollagen-polyurethane mixture rather than only one layer is that thelayered prosthesis is stronger and provides better protection againstpotential fluid leakage. An outer layer containing a silicone elastomeror a similar substance which adds strength to the prosthesis isadvantageous when it is desired to prevent any tendency of theprosthesis to leak in the desired application. Examples of substanceswhich may be used in place of, or in addition to silicone include otherpolyurethanes or elastomer polymers with similar elastic properties.

Prostheses comprising layers of the molded collagen-polyurethane mixturemay be constructed so that the collagen-polyurethane layers arephysically attached to each other or they may be constructed with alayer of a different substance, polymer, mesh or netting between thelayers. It is only necessary that, in the final product, the variouslayers do not separate under physiological conditions. Different layersmay be impregnated with different drugs, medicinal substances or otherbiological agents to provide a localized delivery of these agents tospecific surfaces of the prosthesis. The different layers may alsocomprise compositions with differing rates of biodegradability.

Medicinal substances such as drugs, hormones, immunosuppressants,biological agents and the like may be included in the collagen solutionand incorporated into the molded prosthesis structure to provide alocalized exposure or a controlled delivery of said substance in thehost at the site of the implant. Appropriate antibiotic solutionsinclude penicillin, 10,000 U/ml; streptomycin, 10,000 mcgs/ml; orfungizone, 25 mcgs/ml.

In a preferred embodiment, the conduit of the invention is used for avascular prosthesis in the implantation of a vascular graft, smalldiameter vascular graft, atrial patch, prosthetic valve cusp or arterialpatch. In another preferred embodiment, the invention is used to replaceor graft a blood vessel with a small diameter, especially one less than5 mm in diameter.

The prosthesis or conduit of the invention is also useful as a ureteral,urethral or biliary prosthesis. As is understood by those skilled in theart, the composition of the invention results in a conduit which wouldbe applicable to any biological drain, catheter, cannula, shunt, tube,or tube-like organ such as the windpipe or intestine.

The prosthesis of the invention is also useful as a soft-tissuesubstitute for example, in bioartificial systems including endocrine orhepatic transplantation, soft-tissue prothetic materials and bonegrafts.

In another embodiment, the composition of the invention is used tocreate a sustained-release vehicle to deliver a prolonged dose of acompound internally. Such a vehicle would be useful to deliverprolonged, localized doses of drugs, medical agents, biological agents,and the like used in the treatment of many diseases, including heartdisease, glaucoma, angina, motion sickness, narcotics addiction, cancer,diabetes, pollen allergies and high blood pressure. In addition, such avehicle would be useful for the sustained release of such compounds inthe digestive system, for example, for weight control; or, for thedelayed release of drugs till they passed the stomach. The compositionof the invention would also be capable of providing a unit containing amatrix system to prolong the effectiveness of cosmetics, pesticides,fertilizers, detergents, cleaning agents and the like.

When embodied in a layered form, the sustained-release vehicle of theinvention may be used to deliver different compounds at different ratesor to different sites of action. For example, a compound of interestincorporated into the outer layer of the vehicle may diffuse from thevehicle faster than one contained only in an inner layer. Alternatively,a vehicle may be designed to deliver one drug to the stomach and one tothe lower intestine, for example, by incorporating the drug designed forrelease in the lower intestine into an inner layer of the vehicle andincorporating the drug designed for release in the stomach into theouter layer.

Having now generally described this invention, the same will be betterunderstood by reference to certain examples which are included hereinfor purposes of illustration only and are not intended to be limitingunless otherwise specified.

EXAMPLE 1 Procedure for Making a Layered Graft ofPolyurethane/Collagen/Silicone Elastomer

Silicone tubing to be used as the mandrel is placed on a rotating devicesuch as a lathe. Hypol 2002 is mixed with the stock collagen solution ina 1:1 ratio (the stock solution is 1 mg collagen/ml). Thepolyurethane/collagen mixture is layered onto the rotating mandrel andallowed to cure while continuously rotating, normally for approximately30 minutes.

A mixture of polyurethane and silicone is made by mixing equal amountsof Hypol 2002 and Dow Corning #92-009 Silicone Dispersion Fluid, thenmixing in the Stock Saline Solution (0.9% NaCl, 2 units/ml heparin and 2ml/liter 0.1% Triton X-100) (without collagen). Each constituentcomprises one-third of the total mixture. The polyurethane/siliconemixture is then layered onto the rotating mandrel over the first layerof cured Hypol/collagen and allowed to cure while rotating.

Approximately 4g of Silicone Dispersion #92-009 is mixed withapproximately 2-3 g of table salt prior to curing to ensure that thefinal silicone layer will be porous. The Silicone Dispersion saltmixture is then layered onto the rotating mandrel over the previouslayers. This coating is allowed to cure while rotating and takes hoursto cure completely. Normally this layer is allowed to cure overnight.The rotation can be terminated after approximately 2 hours after whichthe silicone elastomer will hold its form without further rotation. Thesalt does not dissolve in the silicone dispersion and after the layercures, crystals of salt can be visually observed.

The mandrel-with-graft can now be removed from the lathe and soaked indistilled water to dissolve out the salt. Removing the salt crystalsresults in a porous material compatible with the uses described in theapplication. The resultant silicone elastomer layer is porous yet thinand strong enough to resist tearing at the site of sutures.

The graft can now be removed from the mandrel and stored. The graft canbe stored dry or it can be stored in the saline stock solution (withantibiotics). If it is stored dry it is necessary to rehydrate the graftprior to use.

EXAMPLE Tensile Measurements

Graft prototypes were made by hand by smoothly mixing the prepolymerHypol 2000 with an equal volume of stock solution containing 1 mg/mlcollagen dissolved in lactated Ringer's solution (or 0.9% NaCl)containing 2 units/ml heparin and 2 ml/liter 0.1% Triton X-100. A glassrod was used for the mixing and allowed to remain in the test tube asthe mandrel for the graft's lumen. Smooth mixing, rather than vigorousshaking, was necessary to avoid generating large bubbles.

After being mixed in a cup using a wooden tongue depressor, thepolyurethane-collagen mixture was poured into a tubular mold to reactand cure. Virtually any size graft can be made this way. As the mixturefoamed, it overflowed the mold through the longitudinal opening throughwhich the fluid was poured. After the material cured, the excess wastrimmed off. The graft was then lifted out of the mold on the pieceforming the lumen. That piece was then pulled away leaving the tubularcast. Any remaining excess material was again trimmed away.

The samples were tested for their tensile strength by inserting a ring,0.5 cm in length, cut from the graft into a Tensile Tester (Instron)sample holders.

As shown in FIG. 1, stress and strain testing demonstrated excellentelongation properties (approximately 2x) with very little plasticdeformation before material failure. Prosthesis samples which did nothave the bubbles uniformly distributed throughout their structure wereinferior and gave poor results in the stress and strain testing.

EXAMPLE 3 Compliance Measurements

Tensile strength and elongation measurements for a prosthesis made asdescribed in Example 1 are shown in FIG. 2. Over a range that is two tothree times physiologic, the total graft elongation was approximately40%, or 4 mm. The experimental grafts produced thus far demonstrateapproximately 10% diameter expansion (dynamic compliance) in an in vitrocircuit with flow pressure at 150 mm Hg.

EXAMPLE 4 Biological Compatibility of Hypol

Preliminary cell culture experiments were done to examine the curedHypol 2002 as a host material for endothelial cells. Small discs ofcured Hypol 2002 of approximately 2 cm² were placed into cell culturewells and seeded with canine endothelial cells. The same cell cultureprocedures were followed as are standard in our laboratory for all cellculture experiments. (Shindo, S., et al., J. Vasc. Surg. 6:325-332(1987)). The cells overgrew the Hypol material and grew to confluence infairly short order. This indicates that Hypol is a biologicallyacceptable substrate for endothelial cells and seeded prostheses.

EXAMPLE 5 Animal Implants

Collagen-polyurethane-silicone prostheses as prepared in Example 1 wereimplanted in the carotid position in six sheep. Grafts subsequentlyharvested after four weeks were observed to maintain satisfactoryintegrity and patency for use as vascular prostheses.

Having now fully described this invention, it will be understood bythose with skill in the art that the scope may be performed within awide and equivalent range of conditions, parameters, and the like,without affecting the spirit or scope of the invention or of anyembodiment thereof.

What is claimed is:
 1. A prosthesis useful for implantation in ananimal, wherein said prosthesis comprises:at least one layer of auniform mixture of closed-cell foam polyurethane and collagen in theshape of an elongated hollow body tube, said hollow body tube being openat both ends and defining a confined-flow passageway.
 2. The prosthesisof claim 1, wherein said prosthesis further comprises two or more layersof a uniform mixture of foam polyurethane and collagen.
 3. Theprosthesis of claim 1, wherein said prosthesis further comprises anouter layer which contains a silicone elastomer.
 4. The prosthesis ofclaim 1, wherein the confined-flow passageway has an inner diameter of10 mm or less.
 5. The prosthesis of claim 1, wherein the confined-flowpassageway has an inner diameter of 5 m or less.
 6. The prosthesis ofany one of claims 2-5, wherein said prosthesis contains an antibiotic.7. The prosthesis of any one of claims 2-5, wherein said prosthesiscontains a hormone.
 8. The prosthesis of any one of claims 2-5, whereinsaid prosthesis contains an immunosuppressant agent.
 9. A method forimplanting a vascular prosthesis which comprises suturing a prosthesishaving at least one layer containing a uniform mixture of foampolyurethane and collagen into a blood vessel, tissue or other organ.10. A method for implanting a ureteral prosthesis which comprisesreplacing the ureter, or a portion thereof, with a prosthesis having atleast one layer containing a uniform mixture of foam polyurethane andcollagen.
 11. A method for implanting a urethral prosthesis whichcomprises replacing the urethra, or a portion thereof, with a prosthesishaving at least one layer containing a uniform mixture of foampolyurethane and collagen.
 12. A method for implanting a biliaryprosthesis which comprises replacing the bile duct, or a portionthereof, with a prosthesis having at least one layer containing auniform mixture of foam polyurethane and collagen.
 13. The method of anyone of claims 9-12, wherein said prosthesis further comprises two ormore layers of a uniform mixture of foam polyurethane and collagen. 14.The method of any one of claims 9-12, wherein said prosthesis furthercomprises an outer layer which contains a silicone elastomer.
 15. Themethod of any one of claims 9-12, wherein said prosthesis furthercomprises closed-cell foam polyurethane.